Insulin resistance (IR) is the modifiable metabolic state underlying type 2 diabetes mellitus (DM2), cardiovascular disease (CVD), and Alzheimer?s disease. Studies to date have shown significantly increased risk for Mild Cognitive Impairment and Alzheimer?s disease in the presence of DM2, as well as overt cognitive, morphological and functional brain abnormalities in cognitively-normal male and female individuals with IR. While DM2 can be modified with pharmacological and/or behavioral interventions, IR (a precursor to DM2), is a reversible condition. Of notable concern is that rates of IR, and pre-diabetes, are ever increasing; as of 2007, the CDC estimated 57 million (26%) of American adults have it. Further mechanistic studies on the deleterious effects of IR on Alzheimer?s disease risk are needed. Better, more effective and early detection of Alzheimer?s disease risk will strongly depend on disentangling the effects of non-modifiable genetic biomarkers, such as APOE4 and familial risk, from modifiable biomarkers, such as IR. This proposal aims to advance our understanding of the mechanisms of insulin action in the living human brain, before overt neurodegeneration has begun, thus identifying the earliest signs of Alzheimer?s disease. It?s not known whether IR can predict cognitive decline in individuals younger than age 50 without overt mental illness. We propose to use an innovative accelerated longitudinal design (ALD) to characterize trajectories of cognitive and neural biomarkers and to: 1) describe baseline cognitive and neural biomarkers of brain function across the spectrum of IR in persons ages 25-50; 2) assess how the baseline IR and change in IR at a younger age affects the pattern of decline in cognitive and neural biomarkers and 3) explore the effects of baseline IR on changes in cognitive and neural variables of interest as moderated by non-modifiable risk factors for Alzheimer?s disease (gender, and APOE4/family history). Utilizing an accelerated longitudinal design (ALD) we will recruit overweight/obese individuals (total N=135) aged 25-50. Based on semi-longitudinal data, this design will allow us to examine outcome development over 25 years between ages 25-50 after 3-year follow-up. All subjects will undergo baseline qualitative measure of IR, cognitive assessments and multimodal magnetic resonance imaging (MMRI). Neuropsychological evaluation will focus on cognitive flexibility/set shifting tests reflecting hippocampal connectivity to the medial prefrontal region. MMRI will include memory-related hippocampal function and connectivity (measured with task- and resting-state fMRI) and hippocampal volumes. This project will help to identify adults at risk for Alzheimer?s disease and afford a unique opportunity to assess whether IR mediates cognitive and correlating neural processes decades before the age-related cognitive impairment, Mild Cognitive Impairment or Alzheimer?s disease become apparent.